Low brainstem levels of serotonin and the enzyme that makes it could be behind sudden infant death syndrome (SIDS), researchers suggested.

Action Points

Explain to interested patients that this study supports serotonin as part of the mechanism of SIDS, but how this can be exploited in prevention of SIDS remains to be seen.

Low brainstem levels of serotonin and the enzyme that makes it could underlie sudden infant death syndrome (SIDS), researchers suggested.

In an autopsy study, SIDS cases showed 26% lower serotonin levels in two major components of the medulla's serotonin system -- the raphé obscurus (P=0.05) and paragigantocellularis lateralis (P=0.04) -- compared with age-adjusted controls who died from known causes.

These brainstem circuits control breathing, blood pressure, and heart rate during sleep, Hannah C. Kinney, MD, of Children's Hospital Boston, and colleagues reported in the Feb. 3 issue of the Journal of the American Medical Association.

A baby with an abnormality in control of these systems might not be able to respond to a life-threatening challenge like asphyxia by rousing from sleep or turning its head the researchers explained.

SIDS occurs in the "critical first year of life, when homeostatic systems are still maturing," they noted.

Mary McClain, RN, MS, of Boston University Medical Center, who counsels families that have lost a baby to SIDS, commented that these findings help establish the biological basis for urging parents to place their babies on their backs to sleep.

The researchers obtained tissue samples from autopsies of 41 children who died from SIDS, seven who died acutely from known causes (including a car accident, drowning, pneumonia, and unsuspected congenital heart disease), and five who died in the hospital with chronic conditions causing hypoxia-ischemia.

SIDS cases had mean serotonin levels of 31.4 pmol/mg of protein in the paragigantocellularis lateralis, compared with 40.0 pmol/mg among the controls who died acutely (P=0.04).

These abnormalities in the medulla did not appear to involve the catecholamine system. Catecholamine levels were similar between SIDS cases and controls.

Nor was there evidence for excessive degradation of dopamine or neurotransmitter turnover in SIDS cases, supporting the idea that the key abnormality is reduced synthesis of serotonin, the researchers said.

Another marker of serotonin function -- tryptophan hydroxylase (TPH2), the key enzyme involved in synthesis of serotonin -- also supported this conclusion, with 22% lower levels in the raphé obscurus in SIDS than in controls (P=0.03).

Serotonin receptor binding was 29% to 55% lower in three medullary nuclei that receive serotonin projections, notable for a decrease in binding with older age in SIDS cases, but not controls, the researchers noted.

Given similar findings in three previous investigations, this "may reflect a progressive decrease with age in those infants with the 'SIDS abnormality,'" they wrote. Or it's possible that those with a "stronger abnormality take longer to outgrow the risk period for SIDS and continue to die at older ages," Kinney's group wrote.

Likewise, serotonin receptor binding in infants who died from SIDS was significantly lower in those without known risk factors for SIDS, such as sleeping face down, "suggesting that additional risk factors are necessary to precipitate death when the medullary serotonin system is less compromised," they added.

Although repetitive apnea and agonal impaired gasping before death have been reported in some SIDS cases, chronic impaired oxygenation in the hospitalized children in the study produced a very different serotonin pattern than that seen in SIDS.

Children who died with chronic hypoxia conditions had 55% higher serotonin levels in the raphé obscurus (P=0.02) and 126% higher levels in the paragigantocellularis lateralis (P=0.002) than the SIDS cases.

They also had 640% higher dopamine levels in the raphé obscurus than the SIDS cases (P=0.006).

This suggested "that the primary mechanisms underlying serotonin abnormalities in SIDS are not mediated by chronic hypoxia-ischemia," Kinney's group wrote.

The researchers cautioned that their neurotransmitter measurements may have been off somewhat due to prolonged postmortem intervals.

They also warned that the study was limited by inability to perform these measurements at the synapse in postmortem tissues and by the small sample of controls.

The study was supported by the First Candle/SIDS Alliance, CJ Martin Overseas Fellowship (National Health and Medical Research Council of Australia), CJ Murphy Foundation for Solving the Puzzle of SIDS, CJ Foundation for SIDS, National Institute of Child Health and Development, and the Developmental Disabilities Research Center at Children's Hospital Boston.

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